Is COMP p.Thr660Arg (c.1979C>G) pathogenic?

COMP p.Thr660Arg (c.1979C>G) is classified Conflicting classifications of pathogenicity in COMP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.6174); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Thr660Arg (c.1979C>G)?

COMP p.Thr660Arg (c.1979C>G) is associated with Inborn genetic diseases, multiple epiphyseal dysplasia type 1, pseudoachondroplasia (ClinVar).

How common is COMP p.Thr660Arg (c.1979C>G) in the general population?

COMP p.Thr660Arg (c.1979C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about COMP p.Thr660Arg (c.1979C>G)?

AlphaMissense predicts likely pathogenic (score 0.6174) — an in-silico prediction, not a clinical call.

COMP p.Thr660Arg

c.1979C>G · rs150534218 · VCV328611

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6174 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6174	likely pathogenic
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00863%

Overall 0.00855% 138/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.0108%	9,292
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,932

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COMP
Protein: p.Thr660Arg
Coding: c.1979C>G
MANE Select: NM_000095
dbSNP: rs150534218
Type: single nucleotide variant
Location: chr19:18784299 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 660: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a disulfide bond

Full COMP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia type 1 pseudoachondroplasia

Similar variants

COMP p.Thr660Pro Uncertain significance ★ ⚠ same residue
COMP p.Thr660Ala Uncertain significance ★★ ⚠ same residue
COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp273Val Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/comp-p-thr660arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown